Mebendazolium mesylate anhydride salt: rational design based on supramolecular assembly, synthesis, and solid-state characterization.

The design mebendazole (MBZ) multicomponent systems is important to obtain new materials that incorporate the API (active pharmaceutical ingredient) with better thermal stability, avoiding the interconversion of desmotropes. Interestingly, the presence of water molecules in the mebendazolium mesylate monohydrate prevents the formation of the R22(8) supramolecular synthon, found in all mebendazolium salts with polyatomic counterions. Here, we designed a new mebendazolium mesylate anhydrous salt based on statistical scrutiny of all mebendazole crystal structures identified in the literature and an exhaustive analysis of the conformational and geometrical requirements for the supramolecular assembly. The synthesis of this new salt and its solid-state characterization through single-crystal X-ray diffraction and complementary techniques are presented. As expected, mebendazole recrystallization in methanol with methanesulfonic acid - a Food and Drug Administration accepted coformer - in the absence of water yields a mesylate anhydrous salt with 1 : 1 stoichiometry. This new salt crystallizes in the P212121 (19) space group. The main intermolecular interactions found in the crystal structure are the hydrogen bonds that form a R22(8) supramolecular motif that assembles the ionic pairs. Additional non-classical H-bond, as well as π⋯π and carbonyl⋯cation interactions, contribute to the final stabilization of the crystal packing. This new salt is stable up to 205 °C when it undergoes the endothermic loss of the ester moiety to yield 2-amino-5-benzoylbenzimidazole. Moreover, preliminary dissolution experiments in aqueous 0.1 mol L-1 HCl suggest an apparent solubility of mebendazolium mesylate anhydride 2.67 times higher than that of the preferred for pharmaceutical formulations MBZ form C.

Crystalline and amorphous famotidine malate as pathways to prevent polymorphic transformation with improved dissolution.

Famotidine (FMT) is an orally administered histamine H2-receptor blocker with limited bioavailability since it exhibits low solubility and low permeability. In addition, the recent withdrawal of ranitidine from the market, makes famotidine an interesting candidate to obtain solid forms with improved pharmacokinetic performance. In this work, crystal engineering concepts and the co-amorphous formation strategy were applied to obtain two novel solids. Crystalline famotidine malate (FMT-MT) and a vitreous phase (FMT-MTa) were prepared by solvent evaporation and mechanochemical synthesis, respectively. FMT-MT (monoclinic, S.G. P21/n) crystallizes with one FMT and one co-former molecules in the asymmetric unit forming a (R228) structural motif. FMT-MT resulted in a salt by proton transfer from one malic carboxylic group to the guanidine moiety of FMT. The three-dimensional packing is described as undulating layers of alternated FMT+ and MT- running along the a direction. FMT-MTa shows the inherent features of amorphous phases according to powder X-ray diffraction and DSC analysis. The higher physical stability was found for amorphous samples maintained at 4 °C up to 60 days. The solubility assays in water, indicate that FMT-MT and FMT-MTa are 2.02 and 2.68-fold more soluble than the marketed polymorph, whereas similar values were obtained in simulated gastric fluid.

Rational Design of a Famotidine-Ibuprofen Coamorphous System: An Experimental and Theoretical Study.

Famotidine (FMT) and ibuprofen (IBU) were used as model drugs to obtain coamorphous systems, where the guanidine moiety of the antacid and the carboxylic group of the nonsteroidal anti-inflammatory drug could potentially participate in H-bonds leading to a given structural motif. The systems were prepared in 3:7, 1:1, and 7:3 FMT and IBU molar ratios, respectively. The latter two became amorphous after 180 min of comilling. FMT-IBU (1:1) exhibited a higher physical stability in assays at 4, 25, and 40 °C up to 60 days. Fourier transform infrared spectroscopy accounted for important modifications in the vibrational behavior of those functional groups, allowing us to ascribe the skill of 1:1 FMT-IBU for remaining amorphous to equimolar interactions between both components. Density functional theory calculations followed by quantum theory of atoms in molecules analysis were then conducted to support the presence of the expected FMT-IBU heterodimer with consequent formation of a R228 structural motif. The electron density (ρ) and its Laplacian (∇2ρ) values suggested a high strength of the specific intermolecular interactions. Molecular dynamics simulations to build an amorphous assembly, followed by radial distribution function analysis on the modeled phase were further employed. The results demonstrate that it is a feasible rational design of a coamorphous system, satisfactorily stabilized by molecular-level interactions leading to the expected motif.

Preparation and Physical Characterization of a Diclofenac-Ranitidine Co-precipitate for Improving the Dissolution of Diclofenac.

Mixing aqueous solutions of sodium diclofenac (DIC-Na) and ranitidine hydrochloride (RAN·HCl) afforded an off-white solid (DIC-RAN) that was investigated from the microscopic, thermal, diffractometric, spectroscopic, and functional (chemometrics-assisted dissolution) points of view. The solid has a 2:1 (DIC:RAN) molar ratio according to (1)H nuclear magnetic resonance spectroscopy. It is thermally stable, displaying a broad endothermic signal centered at 105°C in the thermogram, and its characteristic reflections in the powder X-ray diffractogram remained unchanged after a 3-month aging period. Scanning electron microscopy micrographs uncovered its morphology, whereas the spectral data suggested an interaction between the carboxylic acid of DIC and the alkyldimethylamino moiety of RAN. The dissolution of DIC-RAN was monitored at different pH values by an ultraviolet/chemometrics procedure, being complete within 5 min at pH 6.8. This compares favorably with the dissolution of a DIC-Na sample of the same particle size.

Solid-state supramolecular synthesis based on the N-H O heterosynthon: an approach to solve the polymorphism problem in famotidine.

Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional π-stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.

Mebendazole mesylate monohydrate: a new route to improve the solubility of mebendazole polymorphs.

Mebendazole mesylate monohydrate, a new stable salt of mebendazole (MBZ), has been synthesized and fully characterized. It was obtained from recrystallization of MBZ forms A, B, or C in diverse solvents with the addition of methyl sulfonic acid solution. The crystal packing is first organized as a two-dimensional array consisting of rows of alternating MBZ molecules linked to columns of mesylate ions by hydrogen bonds. The three-dimensional structure is further developed by classical intermolecular interactions involving water molecules. In addition, nonclassical contacts are also found. The vibrational behavior is consistent with the crystal structure, the most important functional groups showing shifts to lower or higher frequencies in relation to the MBZ polymorphs. Thermal analysis indicates that the compound is stable up to 50°C. Decomposition occurs in five steps. Solubility studies show that the title compound presents a significant higher performance than polymorph C. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3528-3538, 2013.

Structure-directing and template roles of aromatic molecules in the self-assembly formation process of 3D holmium-succinate MOFs.

Two new holmium-succinate frameworks have been synthesized by hydrolysis in situ of the succinylsalicylic acid under different hydrothermal conditions. Compound 1, [Ho(2)(C(4)H(4)O(4))(3)(H(2)O)(2)]·0.33(C(7)H(6)O(3)), P ̅i space group, has a novel structure composed by 1D-SBUs consisting of [HoO(9)] chains of polyhedra linked by the succinate ligands giving a 3D framework. Compound 2, [Ho(2)(C(4)H(4)O(4))(3)(H(2)O)(2)], also belonging to the P ̅i space group, has a denser structure. The role of the in-situ-generated salicylic acid on formation of both structures is studied by means of a synthesis design methodology. A topological study of the new holmium succinate compounds in comparison with the previously reported 3D holmium-succinate framework is performed here.

Thermodynamic and kinetic control on the formation of two novel metal-organic frameworks based on the Er(III) ion and the asymmetric dimethylsuccinate ligand.

Two new layered polymeric frameworks have been synthesized under different hydrothermal conditions and characterized by single-crystal X-ray diffraction, thermal analysis, and variable temperature-Fourier Transform Infrared Spectroscopy (VT-FTIR). The compound I, with formula [Er(2)(dms)(3)(H(2)O)(4)], has a triclinic cell with parameters a = 5.8506 A, b = 9.8019 A, c = 11.9747 A, alpha = 70.145 degrees , beta = 80.234 degrees , and gamma = 89.715 degrees , and the compound II, [Er(2)(dms)(3)(H(2)O)], is monoclinic and its cell parameters are a = 11.1794 A, b = 18.2208 A, c = 12.7944 A, beta = 112.4270 degrees , where dms = 2,2-dimethylsuccinate ligand. A theoretical study including energy calculations of the dms conformers was carried out at the Density Functional Theory (DFT-B3LYP) level of theory, using the 6-311G* basis set. Further calculations of the apparent formation energies of I and II crystalline structures were performed by means of the periodic density functional theory, using DF plane-waves. The analysis of the structural features, theoretical relative stabilities, and the influence of synthesis conditions are presented here. The heterogeneous catalytic activity of the new compounds is tested and reported.

Reversible breaking and forming of metal-ligand coordination bonds: temperature-triggered single-crystal to single-crystal transformation in a metal-organic framework.

Yb(C(4)H(4)O(4))(1.5)] undergoes a temperature-triggered single-crystal to single-crystal transformation. Thermal X-ray single-crystal studies showed a reversibly orchestrated rearrangement of the atoms generated by the breaking/formation of coordination bonds, in which the stoichiometry of the compound remains unchanged. The transformation occurs on heating the crystal at approximately 130 degrees C. This uncommon behavior was also studied by thermal methods, FTIR spectroscopy, and thermodiffractometry. Both polymorphs, alpha (room-temperature form) and beta (high-temperature form), are proven to be active heterogeneous catalysts; the higher catalytic activity of beta is owed to a decrease in the Yb coordination number. A mechanism based on spectroscopic evidence and involving formation of the active species Yb-O-OH is proposed for the sulfide oxidation.

Intermolecular contacts influencing the conformational and geometric features of the pharmaceutically preferred mebendazole polymorph C.

Mebendazole (MBZ) is a common benzimidazole anthelmintic that exists in three different polymorphic forms, A, B, and C. Polymorph C is the pharmaceutically preferred form due to its adequated aqueous solubility. No single crystal structure determinations depicting the nature of the crystal packing and molecular conformation and geometry have been performed on this compound. The crystal structure of mebendazole form C is resolved for the first time. Mebendazole form C crystallizes in the triclinic centrosymmetric space group and this drug is practically planar, since the least-squares methyl benzimidazolylcarbamate plane is much fitted on the forming atoms. However, the benzoyl group is twisted by 31(1) degrees from the benzimidazole ring, likewise the torsional angle between the benzene and carbonyl moieties is 27(1) degrees. The formerly described bends and other interesting intramolecular geometry features were viewed as consequence of the intermolecular contacts occurring within mebendazole C structure. Among these features, a conjugation decreasing through the imine nitrogen atom of the benzimidazole core and a further resonance path crossing the carbamate one were described. At last, the X-ray powder diffractogram of a form C rich mebendazole mixture was overlaid to the calculated one with the mebendazole crystal structure.